Safety and tolerability of lamotrigine for bipolar disorder.

Tolerability and safety are important considerations in optimising pharmacotherapy for bipolar disorder. This paper reviews the tolerability and safety of lamotrigine, an anticonvulsant recommended in the 2002 American Psychiatric Association guidelines as a first-line treatment for acute depression in bipolar disorder and one of several options for maintenance therapy. This paper reviews the tolerability and safety of lamotrigine using data available from a large programme of eight placebo-controlled clinical trials of lamotrigine enrolling a total of nearly 1800 patients with bipolar disorder. This review is the first to collate all the safety information from these clinical trials, including data from four unpublished studies. The results these trials in which 827 patients with bipolar disorder were given lamotrigine as monotherapy or adjunctive therapy for up to 18 months for a total of 280 patient-years of exposure demonstrated that lamotrigine is well-tolerated with an adverse-event profile generally comparable with that of placebo. The most common adverse event with lamotrigine was headache. Lamotrigine did not appear to destabilise mood and was not associated with sexual adverse effects, weight gain, or withdrawal symptoms. Few patients experienced serious adverse events with lamotrigine, and the incidence of withdrawals because of adverse events was low. Serious rash occurred rarely (0.1% incidence) in the clinical development programme including both controlled and uncontrolled clinical trials. These findings - considered in the context of data showing lamotrigine to be effective for bipolar depression - establish lamotrigine as a well-tolerated addition to the psychotropic armamentarium.     

Organ slice viability extended for pathway characterization: an in vitro model to investigate fibrosis.

Liver slice viability is extended to 96 h for rat, expanding the use of this in vitro model for studying mechanisms of injury and repair, including pathways of fibrosis. The contributing factors to increased organ slice survival consist of the use of a preservation solution for liver perfusion and slice preparation, obtaining rats that are within the weight range of 250-325 g, placing a cellulose filter atop the titanium mesh roller-insert to support the slice, and maintaining the slices in an optimized culture medium which is replaced daily. The liver slices remain metabolically active, synthesizing adenosine triphosphate (ATP), glutathione, and glycogen, and exhibit preserved organelle integrity and slice morphology. Slice preparation results in 2-cut surfaces which likely triggers a repair and regenerative response. The fibrogenic pathways are evident by the activation of stellate cells, the proliferation of myofibroblast-like cells, and an increased collagen deposition by 48 h. Markers indicative of activated stellate cells, alpha-smooth muscle actin, collagen 1a1, desmin, and HSP47 are substantiated by real time-PCR. Increased staining of alpha-smooth muscle actin initially around the vessels and by 72-96 h in the tissue is accompanied by increased collagen staining. Microarray gene expression revealed extracellular matrix changes with the up-regulation of cytoskeleton, filaments, collagens, and actin genes; and the down-regulation of genes linked with lipid metabolism. The improvements in extending liver slice survival, in conjunction with its three-dimensional multi-cellular complexity, increases the application of this in vitro model for investigating pathways of injury and repair, and fibrosis.     

Some properties of marrow derived adherent cells in tissue culture

It has previously been shown that monolayer cultures derived adherent cells (MDAC), apparently consisting of fibroblasts, macrophages, epithelioid cells, and fat cells, can support long-term stem cell proliferation in vitro. In the present study, the hematopoietic support capability of murine MDAC monolayers was confirmed and the cultured cells further characterized with respect to the following properties: esterase I activity, complement (C3) receptors, IgG (Fc) receptors, colony stimulating activity (csa) production, and collagen synthesis. The cultures were also examined immunohistochemically to localize fibronectin, laminin, and collagen synthesis and to identify the collagen subtypes synthesized. MDAC morphology was as described in previous studies, although fat cells were few in number. It was found that MDAC included some cells with esterase I activity and C3 receptors. Fc receptors were not, however, detected, nor did the cultures produce csa, indicating that mononuclear phagocytes were not present. MDAC synthesized collagen types I and III and also fibronectin. Staining for epithelial basement membrane proteins (collagen types IV and V and laminin) was negative. The results indicate that the vast majority of these cultured MDAC were fibroblasts.     

Gonadotropin-inhibitory hormone neurons interact directly with gonadotropin-releasing hormone-I and -II neurons in European starling brain

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic dodecapeptide (SIKPSAYLPLRF-NH(2)) that directly inhibits gonadotropin synthesis and release from quail pituitary. The action of GnIH is mediated by a novel G-protein coupled receptor. This gonadotropin-inhibitory system may be widespread in vertebrates, at least birds and mammals. In these higher vertebrates, histological evidence suggests contact of GnIH immunoreactive axon terminals with GnRH neurons, thus indicating direct regulation of GnRH neuronal activity by GnIH. In this study we investigated the interaction of GnIH and GnRH-I and -II neurons in European starling (Sturnus vulgaris) brain. Cloned starling GnIH precursor cDNA encoded three peptides that possess characteristic LPXRF-amide (X = L or Q) motifs at the C termini. Starling GnIH was further identified as SIKPFANLPLRF-NH(2) by mass spectrometry combined with immunoaffinity purification. GnIH neurons, identified by in situ hybridization and immunocytochemistry (ICC), were clustered in the hypothalamic paraventricular nucleus. GnIH immunoreactive fiber terminals were present in the external layer of the median eminence in addition to the preoptic area and midbrain, where GnRH-I and GnRH-II neuronal cell bodies exist, respectively. GnIH axon terminals on GnRH-I and -II neurons were shown by GnIH and GnRH double-label ICC. Furthermore, the expression of starling GnIH receptor mRNA was identified in both GnRH-I and GnRH-II neurons by in situ hybridization combined with GnRH ICC. The cellular localization of GnIH receptor has not previously been identified in any vertebrate brain. Thus, GnIH may regulate reproduction of vertebrates by directly modulating GnRH-I and GnRH-II neuronal activity, in addition to influencing the pituitary gland.     

Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene

Fanconi anemia (FA) is a genetically heterogeneous, inherited blood disorder characterized by bone marrow failure, congenital malformations, and a predisposition to leukemias. Because FA cells are hypersensitive to DNA cross-linking agents and have chromosomal instability, FA has been viewed as a disorder of DNA repair. However, the exact cellular defect in FA cells has not been identified. Sequence analysis of the gene defective in group C patients (FAC) has shown no significant homologies to other known genes. The FAC protein has been localized to the cytoplasm, indicating that FAC may either play an indirect role in DNA repair or is involved in a different cellular pathway. Recent evidence has indicated that FA cells may be predisposed to apoptosis, especially after treatment with DNA cross-linking agents. The demonstration that genes can suppress apoptosis has been accomplished by overexpression of such genes in growth factor-dependent cell lines that die by apoptosis after factor withdrawal. Using retroviral-mediated gene transfer, we present evidence that expression of FAC in the hematopoietic factor-dependent progenitor cell lines 32D and MO7e can suppress apoptosis induced by growth factor withdrawal. Flow cytometry and morphologic analysis of propidium iodide stained cells showed significantly lower levels of apoptosis in FAC-retroviral transduced cells after growth factor deprivation. Expression of FAC in both cell lines promoted increased viability rather than proliferation, which is consistent with other apoptosis-inhibiting genes such as Bcl- 2. These findings imply that FAC may act as a mediator of an apoptotic pathway initiated by growth factor withdrawal. Furthermore, the congenital malformations and hematologic abnormalities characterizing FA may be related to an increased predisposition of FA progenitor cells to undergo apoptosis, particularly in the absence of extracellular signals.     

Comparison of the effects of calcium antagonists and converting enzyme inhibitors on renal function under normal and hypertensive conditions

Calcium antagonists decrease the ability of the kidney to autoregulate renal blood flow (RBF) and glomerular filtration rate (GFR). Therefore, when afferent renovascular resistance is elevated, as in essential hypertension, there is a resultant increase in RBF and GFR with the administration of calcium antagonists. These agents also induce a marked natriuresis because of direct tubular action through unknown mechanisms. The natriuresis can be dissociated from renal and systemic hemodynamic actions, indicating that the decreased sodium reabsorption could override other compensatory mechanisms explaining the absence of sodium retention during the treatment. The renal effects of converting enzyme inhibitors (CEIs) can be explained by the reduction of intrarenal formation in angiotensin II. Because the activation of the renin-angiotensin system is mainly responsible for inducing sodium retention during a decrease in systemic blood pressure, CEIs could have a protecting effect without disturbing other homeostatic mechanisms. CEIs decrease efferent glomerular resistance, reducing capillary pressure and thereby reducing GFR. This effect is not translated in sodium retention because the reduction of GFR is mild during captopril administration in kidneys with normal or increased renal perfusion pressure. At low renal perfusion pressure, the reduced glomerular afferent vasoconstriction can compromise GFR, leading to renal insufficiency. Although these situations are not likely to be encountered during the treatment of uncomplicated essential hypertension, in severe hypertension with hypertrophy of pre-glomerular vessels, glomerular perfusion may decrease. Combination therapy of calcium antagonists and CEIs has been reported to be an effective treatment of severe hypertension. Currently, little information is available on the manner in which renal function is affected by simultaneous administration of both drugs.     

Factors that affect human hemopoiesis are produced by T-cell growth factor dependent and independent cultured T-cell leukemia-lymphoma cells

Some laboratory results and clinical situations suggest that human T cells may be important in the regulation of growth of hematopoietic cells. Since the discovery of T-cell growth factor (TCGF), systems are now available for the long-term specific in vitro propagation of mature normal or neoplastic human T cells, providing an opportunity to study the influence of T cells on hematopoiesis. Recently, 24 cell lines from patients with cutaneous T-cell lymphoma (CTCL) and T-cell acute lymphoblastic leukemia (T-ALL) were grown with TCGF and then assessed for release of humoral factors that affect hematopoiesis. Conditioned media (CM) from these cell lines were tested for erythroid burst- promoting activity (BPA) and granulocyte colony-stimulating activity (CSA). BPA was detected in CM from 3/6 cultures of T-ALL patients and 4/6 CTCL cultures. CSA was found in the CM from 6/8 cultures of T-ALL patients, 7/12 CTCL cultures, and 3/4 CTCL cell lines that become independent of exogenous TCGF for growth. The CSA from several of the neoplastic T-cell cultures stimulated high levels of eosinophil colonies, a possible source of the eosinophilia seen in these patients. The ability of continuously proliferating human T lymphocytes, which retain functional specificity and responsiveness to normal humoral regulation, to produce factors that directly or indirectly stimulate myeloid and erythroid colony formation lends further credence to the role of T lymphocytes in regulating hematopoiesis.     

Development of an opinion leader-led HIV prevention intervention among alcohol users in Chennai, India.

In 1999, we began a community-based randomized controlled prevention trial in Chennai, which aims to test the efficacy of HIV prevention messages disseminated through members of an individual's social group called community popular opinion leaders, or CPOLs. We targeted patrons of 100 bars or wine shops in the city of Chennai, India. In this article we report on the process of development of an HIV prevention intervention for wine shop patrons. First, we conducted detailed ethnography to understand social norms and CPOL and social network characteristics, including 41 in-depth interviews among wine shop patrons and gatekeepers. Second, we tailored a generic HIV education training manual to appropriately address the needs of Chennai wine shop patrons. Field-testing involved 16 focus groups with wine shop patrons and 12 sessions of participant observations in wine shops. Finally, we piloted the intervention to determine the appropriateness of the training program and its content among wine shop patrons. Our ethnographic data indicated that wine shops are a common meeting place for men. We were able to identify CPOLs influential in these settings and train them to deliver appropriate prevention messages to their close friends and associates. We found that HIV prevention messages in this population need to dispel misperceptions about HIV transmission, provide strategies and skills to adopt and sustain condom use, and target the role of alcohol in sexual behavior. We outline specific lessons we learned in intervention development in this population.